Tissue regeneration is an important component of the healing process subsequent to disease, trauma, or surgery. In situations where disease or trauma produces bone defect, for example, or where a surgical procedure such as insertion of an autograft or allograft, bone bridge, or bone fusion is used to correct a bone defect, bone regeneration is a central goal of recovery. It is not, however, a goal that is always or easily achieved and much research has been devoted to newer and more effective ways to promote tissue repair and regeneration.
Elimination of joint motion by creation of a bone bridge is a common orthopedic strategy for the treatment of degenerative spine and joint disorders. Failure of spine fusion can occur in as many as forty-five percent of the patients who undergo the procedure, leaving them with continued pain, repeated surgeries, medical costs, and overall therapeutic failure.
Intracellular and extracellular osteoinductive proteins promote bone growth and repair and constitute potential targets for therapeutic use. Such proteins include the bone morphogenetic proteins and the LIM mineralization proteins. BMPs have been shown to stimulate bone growth in vivo and LMPs, particularly LMP-1 and LMP-3, have a more upstream effect on osteoinduction, as evidenced by the fact that inhibition of LMP-1 expression blocks nodule formation that would normally be stimulated by glucocorticoids or BMP-6. Since they are considered “extracellular” proteins, acting via interaction with cell surface receptors, very high doses of bone morphogenetic proteins are required to achieve consistent effects in humans. Since the manufacturing costs of BMPs is generally high, this can mean that the cost of therapy is prohibitive. Therefore, although BMPs have demonstrated efficacy and are a viable therapeutic aid to osteoinduction, it would be beneficial to develop an alternate therapy that might be more cost-effective and possibly even more therapeutically effective.
Delivery of LMPs to the intracellular environment provides an attractive therapeutic regimen. This can be accomplished by transfection of cells with plasmids comprising a nucleotide sequence encoding a LIM mineralization protein, or can be done by infection of target cells with a viral vector carrying the nucleotide sequence of LMP. Each of these techniques has limitations, however. Plasmid transfection generally requires that cells be isolated for transfection and then implanted after transfection. Viral delivery generally requires that the appropriate receptor be located on the surface of the target cell in order to facilitate viral entry into the cell.
There is tremendous potential for the use of osteoinductive proteins and peptides, particularly for the use of those proteins and peptides that act via an intracellular mechanism. What is needed is a method of delivery of effective intracellular osteoinductive proteins and peptides into cells.